PPA synthesis

Synthon · Sat Sep 17, 2005 1:37 am

Hi bees,

SWIM will attempt this synthesis of racemic d,l- nor(iso)ephedrine
(taken from rhodium´s archive):

2-nitro-1-phenyl-1-propanol ala Kamlet:

Benzaldehyde (106.1 g., 1.0 mole) was agitated with sodium bisulfite (100.6 g., 1.06 mole) in 500 ml of water for 30 minutes. Separately, nitroethane (82.5 g., 1.10 mole) was dissolved, with cooling, in a solution made from 50% sodium hydroxide (90.9 g., 1.13 mole) and 155 ml of water. This mixture was added, over a period of 15 minutes, at 25°C, with vigorous agitation to the addition product of benzaldehyde and sodium bisulfite. After stirring overnight, the lower layer was discarded. HPLC analysis of the upper layer showed a conversion of 125.4 g. (69.3%) of total 2-nitro-1-phenyl-1-propanol with a (1R*,2S*)-isomer content of 43.9 g. (35.1 %).

2-nitro-phenylpropanol to PPA:

Zinc and Acid method:
Hydrochloric acid (4 moles) is added (with stirring) to a mixture of nitroalcohol (1 mole), zinc dust (4 moles), and 400 ml. of 95% ethanol. The acid is added at such a rate that the temperature remains at 45 degrees or below (several hours are usually required). Stirring is continued for 1-2 hours after completing the addition. The acid solution is extracted with ether to remove non-basic materials. Excess NaOH solution is then added and the free base extracted with ether. The ether solution is dried (MgSO4) evaporated, and the product distilled or crystallized in the usual manner (70-80% yield).

1.) Normally SWIM performs at least 1-2 small scale test reactions before working his way up but that synth sounds not that complicated so in this case a 1 mol PhCHO reaction might be okay. What do you bees think about it?

2.) Must the nitroalcohol be further purified before using it in the reduction and is it possible to store the alky in the fridge before proceeding it to the desired intermediate?

3.) Zn/HCL reduction: Could SWIM use xylol as substitute for diethylether in the cleanup step and extraction of the PPA freebase?
(Because Et02 is too expensive these days and no appropriate solvent with a low bp is available SWIM thought about converting the raceamic ppa to its salt by gassing the xylol/freebase mixture and recrystallize the product several times with MeOH and IPA from anhydrous acetone. That should be sufficient but he read somewhere that the product of this unselective reaction has an more crude tar like consistency than the d,l-norephedrine Swim formerly worked with so maybe the yield losses will be significant. Any suggestions highly appreciated.)

ergoamide · Mon Sep 19, 2005 7:20 am

Yes you could substitute xylene for diethyl ether, although that should be the least of your worries, nitroethane is so watched in so many countries if you can get it i see almost no reason why you couldn't get anything else.

slipknot · Mon Sep 19, 2005 7:34 am

what do they use nitroethane besides drug synthesis

joe_aldehyde · huxleys associate

forget about the Zn reduction, has shitty yields (note: nef reaction) and the workup will give you gray hair - Zn(OH)2 is unfilterable...good luck extracting ANYTHING from this!

ergoamide · Mon Sep 19, 2005 4:56 pm

Synthon · Mon Sep 19, 2005 11:53 pm

@ergoamide

Ether ist available to SWIM, but only in small quantities.

Considering that in this writeup ether was used in extraction of the nitroalcohol intermediate and the end product I assume that from start to finish at least 1 l Eto2 is required for a 1mol reaction. So SWIM has to use xylene or another low cost OTC solvent as a ether substitute.

@Joe_aldehyde

SWIM has no experience with Zn/acid reductions but he heard about the difficulties with the post reaction sludge before. However, both papers that describe reduction of nitrophenylpropanol to ppa via that method mention yields of 70-80%.

Using LAH to reduce the nitroalky might be the best option, but THF and LAH are expensive as fuck and a lot of LAH is needed.
In contrast to Zn/acid reduction is cheap and OTC.

I´m still curious about the best way to clean up the nitroalcohol, any ideas?

joe_aldehyde · huxleys associate

not true that THF/LAH are expensive - depends a lot on where you live. compared to what yields you will get out of the Zn redxn. and the horrible workup, well...you'll see for yourself.
don't expect 70% the first times you try the reduction - it will be more like 10%. apparently the reaction is very sensitive to handling.

bio · Working Bee

........what do they use nitroethane besides drug synthesis............

Stabilizer for drycleaning fluids (PCE etc,) and nitrocellulose solvents.